Use of a Single Implant of Elcometrine (ST-1435), a Nonorally Active Progestin, as a Long Acting Contraceptive for Postpartum Nursing Women

Because of its unique features, the contraceptive effectiveness and tolerance during breast-feeding of 16-methylene-17a-acetoxy-19-nor-4-pregnene-3,20-dione (elcometrine), delivered within a single subdermal capsule of medical grade polydimethylsiloxane, wasinvestigated.Unlike other progestational steroids, elcometrine has no affinity for androgen and estrogen receptors and is inactive by the oral route.

Atotalof 66breast-feedingwomenreceivingel-cometrine by the subdermal route were enrolled in the study, and 69 women who elected to use Copper-T380. intrauterine devices (IUD) served as control subjects. The pregnancy but its failure rate as a method of contraception is high when compared with women and their infants were observed until the end of the first postpartum year.

There were no significant differences in growth and development measurements among the infants in the elcometrine and control groups. The percentage of infants continuing to breast-feed at 3 and 6 months was significantly higher in the elcometrine group. There were no significant differences between the concentration of elcometrine in the mother’s blood and milk. At 75 days, blood levels of elcometrine in the infants were near the undetectable and were significantly lower than the levels in maternal blood or milk (p <0.01). In 15 of 25 infants, blood levels of elcometrine were at the limit of assay sensitivity or undetectable. Two pregnancies occurred in women using IUD, whereas none occurred in those using implants. There were menstrual bleeding irregularities in both groups. A single elcometrine capsule placed subcutaneously at 6-monthly intervals appears to be an effective method of contraception for lactating women and results in blood concentrations of nursing infants at or near undetectable levels.

Maternidade Climerio de Oliveira, Federal University of Bahia, Salvador, Bahia,

Brazil Name and address for correspondence: Professor Elsimar M. Coutinho,

Breast-feeding provides some protection against those of other methods such as the oral contraceptive pill (0C) and progestins administered intramuscularly (injectables).¹ In the postpartum period, nursing women with favorable experience using contraceptive steroids may request continuation of their previous method. However, they are usually advised by their health care providers not to use estrogen-containing oral contraceptives until the baby is completely weaned33 These products contain a synthetic estrogen that can suppress lactation and that has been reported to have adverse effects, such as jaundice and breast development, on the child.3,4

Depo-Provera® (Pharmacia & Upjohn, Kalamazoo, MI), the most widely used injectable progestin, does not suppress milk yield.⁵ Infants exposed to medroxyprogesterone via breast milk have been studied for development and behavioral effects through puberty.

No adverse effects have been noted.⁶ No significant effects were observed on the growth or health of infants whose mothers used the Norplant® system of implants of levonorgestrel in comparative studies with mothers using IUD or barrier methods.⁷ However, no information is available beyond these years. The possible effects of these progestins, ingested by the baby through mother’s milk during the first year of life, need to be observed through late developmental stages, puberty, and beyond.8,9

Elcometrine, also referred to by the Population Council´s trade name of Nestoronee, is a 19-nor progesterone (16-methylene -17a-acetoxy-19 -nor-4-pregnene -3, 20-dione ) related structurally (rings A and B) to the derivatives of 19-nor testosterone, such as norethindrone and levonorgestrel, which are used as progestogens in the conventional oral contraceptive pi11.10 It is also chemically related to 17-a-hydroxy derivatives of progesterone (rings C and D), such as medroxyprogesterone acetate (Depo-Provera) (Figure 1).

Elcometrine inhibits ovulation in women at relatively low doses. Elcometrine can maintain pregnancy in ovariectomized animals, acting as a true progesterone. In view of favorable pharmacology and toxicology, the drug, which had been synthesized in 1967 by chemists of E. Merck AG and has been referred to in other publications as ST-1435, was tested for use as an oral contraceptive.11 However, early clinical studiescarried out in Brazil with Merck’s experimental contraceptive pill containing elcometrine (ST-1435) revealed that the compound was inactive by the oral route. In 1976, elcometrine was shown to be effective in suppressing ovulation when administered parenterally in implant form made with segments of Silastic® Tubing.10,11 A single implant could suppress ovulation for 6 months.11,12 In view of its inactivity by the oral route, it was proposed that the implant could be an alternative for contraception during lactation because the breast-fed baby would not be affected by the compound in the mother’s milk. Elcometrine implants have been shown to provoke no adverse effects on serum lipids, blood pressure, and body weight of nonlactating women.13,15 It remained to be established whether the compound used during lactation would not be transferred in significant amounts to the infant from mother’s milk. In the present study, the effect of a single, subdermal Silastic implant containing 50 mg of elcometrine on the fertility of 66 lactating women and on the health and development of their infants was investigated. In addition, 69 lactating women (who were provided with intrauterine devices) and their infants served as controls.

MATERIALS AND METHODS

The study was conducted at the Maternidade Climério de Oliveira, a teaching hospital of the Faculty of Medicine, Federal University of Bahia, in Salvador, Bahia, Brazil, after approval by the institution’s clinical research review board (IRB).

Subjects

Women aged between 18 and 35 years, having had a singleton term delivery, fully breast-feeding on demand, planning to breast-feed for at least 6 months postpartum and requesting effective contraception, were recruited. Exclusion criteria were: a) conditions requiring regular use of medication; and b) contraindications to the use of oral steroid contraceptives, such as congestive heart failure, hypertension, pelvic infections or tumors, severe anemia, diabetes, liver disease, or any kind of cancer.

Sample Size

In order to detect differences of 400 g in mean weight at 12 months between the two groups for each sex, with a standard deviation of 700 g and a statistical power of 90% and a significance level of 5% in two-sided tests, each group was estimated to require 64 infants.

Admission

Women who were eligible and willing to participate in the study were admitted after signing a written consent form. The form had previously been approved by the Ethics Committee of the Maternity Hospital. Acceptors of the elcometrine subdermal capsule and IUD acceptors were recruited concurrently according to subject preference. The method was initiated at 6 weeks postpartum. Information taken at admission included: a) mother’s height, weight, hemoglobin

level, smoking behavior, and obstetric history; b) infant’s feeding practices, including breast-feeding frequency and any problem relating to infant health; c) records of the infant’s physical examination including weight, arm circumference and triceps skin-fold thickness, as well as development tests; and d) blood and milk samples from the mother served as control values before insertion of the elcometrine capsule.

Follow-up

Visits to the clinic were scheduled for postpartum day 60 and thereafter at monthly intervals until the end of the first postpartum year. The mothers were interviewed on aspects of the contraceptive method they were using, breast-feeding practices, supplementary food given to the infant, and infant health. Infants had the same tests and measurements as at admission. Infant development was assessed according to the age for each infant within each study group (elcometrine or IUD) for passing the following tests: gross motor, vision and fine motor, hearing and language, self-help skills, and social skills. These monitoring tests were the same previously used in a similar World Health Organization (WHO) study in 1994.16

Blood and milk samples were obtained from the mother before implant insertion as a control. After implant insertion, blood samples were drawn at 15 and 75 days of implant use. Breast milk was obtained at 75 days of implant use. A blood sample was drawn fromthe baby in the third month of the study, when the babywas 4 months old and the mother had been using the implant for 75 days. The Ethics Committee limited blood collection from the babies to only once during thestudy and also suggested when it should be done. For this reason, estimation of the blood levels before andafter the third month of the study, was done on the basis of some previous studies on the elcometrine implant. Serum was separated by centrifugation. Serum and breast milk were stored at -20°C until analyzed. Theconcentration of elcometrine in blood and milk was measured by radioimmunoassay by the Steroid Research Laboratory of the Department of Medical Chemistry, University of Helsinki, Finland, according to the procedures previously described.17,18

Discontinuation From the Study

Women were free to request implant removal and to withdraw from the study at any stage.

Contraceptives Used in the Study

The implants were hand-made from medical grade dimethylpolysiloxane (Silastic) tubing made by Dow Corning (Midland, MI; catalog No. 602-235). Segments measuring 4 cm in length and 2.4 mm in diameter were used to make the implants. The segments of Silastic tubing were filled with 50 mg ± 10% of elcometrine, supplied by E. Merck AG, Darmstad, Germany, and sealed at both ends with Silastic medical grade adhesive, type A. Steam sterilization, which had proved effective in previous studies with Silastic implants, was used.” In pilot studies, implants were analyzed before and after steam sterilization, and it was confirmed that no alteration occurred in the steroid content of the implant during this procedure. Subdermal insertion of the implant was performed with an 11-gauge trocar in the gluteal region of subjects after local anesthesia with 2% procaine, as previously described.19 Each capsule was removed and a new one inserted at the end of 6 months of use. The intrauterine device used was the Copper T (TCu380).

Data Management

Characteristics of women and infants at admission and throughout the study were compared between groups (elcometrine versus IUD) using x2 or Wilcoxon tests to evaluate the homogeneity of the groups. For infants, curves of growth for weight, arm circumference, and triceps skin-fold thickness were performed and compared between groups according to contraceptive method. Bar charts were performed to compare level of elcometrine in the mothers’ milk and in the mothers’ and infants’ serum. Bleeding patterns were evaluated according to the Menstrual Diary Analysis Program (MDS) of the World Health Organization, using 90-day reference periods.20

RESULTS

A total of 135 women were enrolled in the study. Of these, 66 chose to use elcometrine implants and 69 had IUD inserted. They were matched by height, weight, age, hemoglobin levels, number of pregnancies, and parity, as shown in Table 1.

Weight and Blood Pressure

No statistically significant differences were found in mean weight or blood pressure between the women in the elcometrine group and those in the IUD group, nor between values recorded at admission versus those recorded during the last month of the study.

Contraceptive Efficacy

Four subjects discontinued before the end of the study in the elcometrine group: three because of menstrual irregularity (prolonged bleeding) and one because of pelvic inflammatory disease and increased ovarian volume. No pregnancies occurred in the elcometrine group. Twelve subjects discontinued in the IUD group: two because of involuntary pregnancy; eight because they failed to return to the clinic regularly with their babies, thereby preventing proper data collection; one who requested removal of the IUD to change to another contraceptive method, and one who requested removal of the IUD because of pelvic pain.

Bleeding Patterns

During the first 3-month interval, five (7.7%) of the 65 women in the elcometrine group remained amenorrheic. During the same time interval, 17 of the 63 women (27% of the IUD users) remained amenorrheic. During the second 3-month interval, the number of women in the elcometrine group who developed amenorrhea increased to 17 (27%). The IUD users remaining amenorrheic during this same time interval decreased from 17 (27%) to eight (12.9%). During the third interval, one third of the women, 22 of 60 (36.7%) in the elcometrine group, developed amenorrhea. Among the women with IUD, four (7.1%) remained amenorrheic. Table 2 shows the various patterns of bleeding during the three 90-day intervals

Breast-feeding Performance

The percentage of babies breast-feeding, exclusively or otherwise, was significantly higher in the elcometrine group (p <0.05) at 3 and 6 months of age. At 9 and 12 months, there was no statistically significant difference between the two groups (Table 3). No difference was found between the two groups regarding the type and frequency of supplementary feeding of babies after the end of exclusive breast-feeding.

Infant Growth

No significant differences in anthropometric measures occurred between the two contraceptive groups. The mean values of weight, arm circumference, and skin-fold thickness at admission and at 3, 6, and 12 months are presented in Table 4.

Infant Development

All infants in the study were tested. Three tests were carried out for gross motor function, six tests for vision and fine motor function, five for hearing and language, two for self-help skills, and three for social skills. The mean age in days at which the infants passed in each test is shown in Table 5. There were no statistical differences between the two groups of children.

Blood Levels of Elcometrine

Elcometrine levels in the blood of the mothers and infants, as well as in milk, are shown in Table 6. Mean values of elcometrine concentration in the blood of mothers was in the range of 463 pmol/L 2 weeks after insertion of the implant and 381 pmol/Lat the end of 10 weeks. The mean concentration of elcometrine in milk was very close to that found in the mothers’ blood, being in the range of 373 pmol/L,a ratio of 0.98. The concentration of elcometrine in infants’ blood, drawn at the end of 10 weeks, was below the assay method detectable level of 13 pmol/L in 15 of 25 subjects (Table 6, Figure 2). If the blood levels of elcometrine in these 15 infants is considered to be at the detectable level of 13 pmol/L, the mean concentration for the group was estimated to be 19.32 ± 2.24 pmol/L, which is about 5% of the mean concentration found in mothers’ milk. Mean maternal serum levels were significantly lower at day 75 when compared with day 15 (p <0.05). There was nosignificant difference between elcometrine levels in breast milk and serum from mothers at day 75. Levels in the serum of babies were significantly lower than levels in the serum of mothers at day 75 (p <0.01).

DISCUSSION

The contraceptive efficacy of lactation is high for women breast-feeding on demand, particularly in those who remain in amenorrhea during the first 6 months postpartum. Diaz et al., in a study of 236 lactating women, found that those who remained amenorrheic had cumulative probabilities of getting pregnant of 0.9% and 17% at 6 and 12 months postpartum, respectively.21 In those whose menstrual cycles were re-established, however, the risk increased to 36% and 55% at 6 and 12 months, respectively. In the present study, which included only urban women who found it difficult to remain breast-feeding on demand, most mothers (57 of 63 [90%] in the elcometrine group, and 59 of 62 [95%] in the IUD group) had discontinued breast-feeding exclusively 6 months after delivery. By the end of 9 months after

delivery, none of the mothers were breast-feeding exclusively, and more than one third of the babies had been weaned (23 in the elcometrine group and 29 in-the IUD group). Most women in the study were, therefore, unprotected by lactational amenorrhea and, if it were not for the protection afforded by the elcometrine implant or the IUD, many of the women exposed would have become pregnant. In the present study, both the IUD and the elcometrine implant prevented pregnancy effectively.The pregnancies that occurred in the two IUD users could be associated with displacement of the device, which is known to occur in some patients during postpartum involution of the uterus. On the other hand, the nonoccurrence of pregnancy in lactating women using elcometrine confirms previous studies in nonlactating women that have shown the elcometrine implants to be effective contraceptives.10-13 In the largest series involving 282 nonlactating volunteers who used a single elcometrine implant as their only form of elcometrine contraceptive at the time of removal of contraception, some of them for as long as 3 years, only one pregnancy occurred over 3373 women-months of use.13 The lactating women in this study demonstrated the acceptability of this form of contraception since all 64 women who remained in the study at the end of 6 months, requested a new elcometrine contraceptive at the time of the first capsule. The insertion and removal procedures for this single implant method proved to be uneventful. The measurement of elcometrine in the blood and milk of the lactating women confirmed ,previous observations that most of the compound passes freely from maternal blood into milk, reaching concentrations which are not statistically different. However, the concentration of elcometrine in the infants’ blood reached a mean of only 19 pmol/L, which represents 5% of the mean levels measured in the mothers’blood. These levels can be expected to be higher during the first weeks after implant insertion and lower during the remaining 14 weeks when the maternal blood levels of elcometrine are declining. At 2 weeks, when the women’s blood level is 462.92 pmol/L, their infants’ blood levels can be estimated to be 23.14 pmol/L, a concentration that is still too low to provoke a biological response. During the last 3 months, the infants’ blood levels should become undetectable in all as the mothers’ blood level decreases to <300 pmol/L. Elcometrine is poorly absorbed by the oral route and rapidly inactivated duringitsfirstpassagethroughtheliver.This characteristic contributes markedly to reduce the possibility of the steroid reaching receptors in the infant’s reproductive system or other sex hormone target cells. The study of Heikinheimo et al.22 used a methodology of HPLC-fractionation and RIA-detection and focused on the in vivo metabolism of elcometrine in the human, after various routes of administration. In women, after parenteral administration of elcometrine either as intravenous injection or transdermal gel, only the elcometrine peak could be detected in the systemic circulation. After oral administration of 10 mg elcometrine to two women, elcometrine as well as two putative metabolites were detected in the systemic serum. The major peak of RIA-detectable material was that of elcometrine, indicating that at that dose, a small fraction of biologically active elcometrine seems to escape from the first-pass metabolism following oral intake. However, the circulating compound was rapidly metabolized and, at 24h, no elcometrine could be detected. Elcometrine has a shorter half-life and faster clearance rate than other progestins that are used as contraceptives.23 After administration as a single intravenous bolus, the plasma disappearance rate of immunoreactive elcometrine had two components with half-lives (mean ± SE) of 3.5 ± 0.5 and 83 ± 14 min, respectively. A study by Kuhnz et al.24 demonstrated that after a single oral administration, gestodene presented a biphasic pattern of disposition with half-lives of 0.13 ± 0.06 and 14.6 ± 4.2 h. Following the same protocol, it was observed that 3-keto-desogestrel levels declined with half-lives of 0.5 ± 0.2 and 17.0 ± 9.3 h. A comprehensive review by Fotherby25 reported a mean elimination half-life of levonorgestrel as 16 h and that of norethindrone as 7 h. The average half-life of elimination of d-norgestrel was reported as 13.5 h.26 After oral administration of 100 lig of elcometrine in fasting women, the highest concentration in plasma was attained at 10 min and reached 423 ± 90 pmol/L. This level was reduced to 50% at 60 min.’ The explanation for this short half-life is elcometrine’s inability to bind to sex hormone-binding globulin (SHBG) or to cortisol-binding globulin (CBG), transport proteins that prolong the biological half-life of many steroid hormones.17The small amount of the steroid reaching the blood of some of the nursing infants in the present study, therefore, can be expected to become undetectable 1-2 h after each feeding. No information is available in the literature regarding the blood levels of medroxyprogesterone acetate in infants breast-feeding in Depo-Provera-treated women. One study carried out in lactating Norplant users reported levels of levonorgestrel in the infants’

blood during the third month after implant insertion of 0.16 ± 0.7 nmol/L.27 The mean blood level of elcometrine in the infants reported in the present study of 19 pmol/L compares favorably with these levels of levonorgestrel, which correspond to 160 pmol/L. These data suggest that elcometrine is an acceptable alternative to both Norplant and Depo-Provera for use by lactating women, involving no discernible risk for the health of their infants.

ACKNOWLEDGMENTS

This study was supported by a grant from South-to-South Cooperation in Reproductive Health, a collaborating research program funded by the Rockefeller Foundation. The authors would like to acknowledge the collaboration of the Steroid Research Laboratory, Institute of Biomedicine of the University of Helsinki, Finland, for the assay of elcometrine in blood and milk samples.

24. Kuhnz W, Schutt B, Power J, Back DJ. Pharmacokinetics and serum protein binding of gestodene and 3-ketodesogestrel in women after single oral administration of two different contraceptive formulations. Arzneimittelforschung 1992;42:1139 – 41.